The overall goal of this application is to train Chloe E. Atreya, MD-PhD, a candidate with an excellent foundation for translational research, to become a leading independent investigator of molecularly targeted inhibitors in preclinical models derived from human tissues, with a goal to improve treatments for patients with metastatic colorectal cancer (mCRC). The proposed research plan incorporates the following training goals: 1) to refine integrated expertise in molecularly targeted therapies, from chemistry to effects on cell signaling and performance in early phase trials, 2) to build expertise in use of patient-derived samples in research, including model development, characterization and genomic analysis 3) to acquire expertise in clinical trial design, including biostatistics and correlative science and 4) to attain professional development in key areas such as management of multidisciplinary teams. The proposed research will address limitations that have hindered therapeutic advancements for patients with mCRC: 1) drug testing in typical preclinical models derived from commercially available CRC cell lines has failed to predict outcomes in CRC patients and 2) the clinical efficacy of individual molecularly targeted inhibitors has been underwhelming, likely because CRC exhibits aberrant signaling in two dominant oncogenic pathways. The candidate's central hypothesis is that combinations of inhibitors targeting key nodes in both pathways upregulated in CRC will be maximally effective independent of baseline signaling or single agent activity. The following specific aims are proposed: 1) to test the effect of combining inhibitors of both oncogenic pathways in CRC patient-derived mouse models, 2) to identify mechanisms of drug resistance and to develop pharmacologic strategies to overcome this resistance, and 3) to determine whether the inhibitor effects observed in CRC patient-derived mouse models are recapitulated in spheroid cultures isolated from tumors, and to expand drug screening in spheroids. The candidate's training and research plan incorporates a combination of coursework, tutorials, mentoring, and hand-on research experience set in the unparalleled academic environment of UCSF, a world-renowned center of excellence in translational medicine and research, including the Helen Diller Family Comprehensive Cancer Center, abundant institutional resources, and a well-integrated community of clinicians and scientists. The candidate's mentor is Howard Hughes Medical Institute investigator, Dr. Kevan Shokat, and her multidisciplinary advisory committee includes distinguished scientists, medical and surgical oncologists. Successful completion of the proposed research will produce compelling preclinical rationale for testing specific targeted inhibitor combinations in patients within biomarker-defined subsets of mCRC. The intermediate-term goal is to open a CRC-specific clinical trial that will serve as the basis for a successful R01 proposal. Long- term goal are for the integrated, patient-derived preclinical platform to inform treatment decisions for the same patients from whose tumor cells the models derived, and to result in more survivors of mCRC.